Many different tissue and organ preservation solutions have been designed, as investigators have sought to lengthen the time that a tissue or organ may remain extra-corporeally, as well as to maximize function of the organ following implantation. Several of the key solutions that have been used over the years include: 1) the Stanford University solution [see, e.g., Swanson, D. K., et al., Journal of Heart Transplantation, (1988), vol. 7, No. 6, pages 456-467 (mentions composition of the Stanford University solution)]; 2) a modified Collins solution [see, e.g., Maurer, E. J., et al., Transplantation Proceedings, (1990), vol. 22, No. 2, pages 548-550; Swanson, D. K., et al., supra (mention composition of modified Collins solution)]; and 3) the University of Wisconsin solution (Belzer, et al., U.S. Pat. No. 4,798,824, issued Jan. 17, 1989). Of those, the University of Wisconsin (UW) solution is currently regarded as the best. (See, e.g., Maurer, E. J., et al., supra).
In addition to the composition of the tissue and organ preservation and maintenance solution, the method of tissue and organ preservation also affects the success of preservation. Several methods of cardiac preservation have been studied in numerous publications: 1) warm arrest/cold ischemia; 2) cold arrest/macroperfusion; 3) cold arrest/microperfusion; and 4) cold arrest/cold ischemia. The first method involves arresting the heart with a warm cardioplegic solution prior to exsanguination and cold preservation, but this method fails because of the rapid depletion of myocardial energy stores during the warm period The second method, which involves arresting the heart with a cold preservation solution, is better; but continuous perfusion of the heart with preservation solution during the storage period fails because of the generation of toxic oxygen radicals. In addition, the procedure of the second method is cumbersome and does not lend itself to easy clinical use. The third method, first described in the journal Nature in 1972 in a system called “trickle perfusion,” is better but also cumbersome. The fourth method of preservation is that of a cold cardioplegic arrest followed by a period of cold immersion of the heart. The fourth method is currently the standard method of cardiac preservation. This fourth method reliably preserves hearts for periods of up to six (6) hours, but less than four (4) hours is considered ideal for this method. Since a longer preservation time is desirable, attempts have been made to improve preservation solutions in such a way as to reliably preserve hearts and other organs for longer periods of time.
Though the University of Wisconsin (UW) solution is currently the industry standard of organ preservation solutions, it is limited in the length of preservation time that it provides. Other solutions have been proposed (see, for example, U.S. Pat. No. 5,552,267 to Stern), however, these have limited use do to the complicated nature of the composition.
The relationship between the long-term patency and endothelial cell preservation has been established. Endothelial cells are known to be important mediators in regulating platelet, anticoagulant, procoagulant, and fibrinolytic functions. These activities of the endothelium allow for control of blood flow as well as thrombosis or blood clotting when there is endothelial injury. Presently, storage solutions are limited in the length of storage (up to 125 minutes) and protection provided to the endothelium. This time frame is insufficient depending on the type of operation being performed (i.e. whether or not a valve replacement or carotid endarterectomy will be needed along with bypass) and on the surgeon performing the operation.
Currently available storage solutions used during bypass surgery vary from normal saline, to physiological salt solutions, to heparinized blood. These solutions do not provide an adequate environment for endothelial or smooth muscle cell support. Normal saline lacks an energy source such as glucose. The pH of saline solutions tend to be low in the 6 to 7 range which is hostile to these fragile cells. Heparinized blood has only been shown to provide adequate storage of veins only up to 90 minutes. All of the currently available solutions are deficient in the combination of free radical scavengers, antioxidants, and nitric oxide synthase substrates that can provide a protective environment for cellular support during this time period where much damage occurs.
The saphenous vein is the most commonly used conduit for coronary artery bypass graft (CABG). The intraoperative preservation of harvested saphenous veins prior to performance of a CABG is believed to be a factor in the protection of the endothelial cells. Indeed, the relationship between the long-term patency and endothelial cell preservation is well established. That is to say, the preservation of endothelial cell viability is vital for inhibiting early pathological changes and the long-term patency of vascular grafts. Zilla P, von Oppell U, Deutsch M. The endothelium: A key to the future. J Card Surg 1993;8:32-60. Restenosis of venous bypass grafts, however, is a common sequelae proximal to vascular endothelial injury that occurs during vein harvest.
The pathological changes leading to ultimate vein graft occlusion and loss in vasomotor function are well documented. Verrier E D, Boyle E M. Endothelial cell injury in cardiovascular surgery: An overview. Ann Thorac Surg 1997;64:S2-8. Endothelial damage appears to be a major cause of graft failure. Specifically, this injury may occur at the time of harvest due to blunt surgical trauma and stretch and due to distension or pressurization prior to anastomosis. Endothelial trauma is also caused by exposure to arterial circulation pressure and oxygenated blood after graft insertion.
Additionally, endothelium damaged or denuded saphenous veins are highly sensitive to the very potent, endothelium derived, circulating endogenous vasoconstrictors. For example, endothelin-1, TXA2, and angiotensin II known to increase during CABG surgery. The increase in vascular tone mediated by these vasoconstrictors may lead to attenuated blood flow, stasis, and predisposition to thrombus formation in venous grafts.
What is needed is a physiological salt solution that would prolong the storage and protection available to harvested bypass conduits and other organs such as those used for transplantation in excess of 24 hours on the basis of cell viability and the integrity of key cell regulatory pathways, including nitric oxide synthesis. In addition devices and methods are also needed that precondition blood vessel grafts without damaging the endothelium of said blood vessels during perioperative graft preparation.